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Characterization of a new synthetic isoflavonoid with inverse agonist activity at the central benzodiazepine receptor

2004; Elsevier BV; Volume: 495; Issue: 2-3 Linguagem: Inglês

10.1016/j.ejphar.2004.05.026

1879-0712

Daniele V.S. Lopes, Rodrigo Rêgo Barros Caruso, Newton G. Castro, Paulo R. R. Costa, Alcides J. M. da Silva, François Noël,

Phosphodiesterase function and regulation

Research aimed at developing selective drugs acting on γ-aminobutyric acid (GABA)A receptors introduced compounds from diverse chemical classes unrelated to the 1,4-benzodiazepines, including flavonoids. These studies also revealed the potential use of inverse agonists as cognition-enhancing agents. Here we report pharmacological properties of the novel synthetic isoflavonoid 2-methoxy-3,8,9-trihydroxy coumestan (PCALC36). PCALC36 displaced [3H]flunitrazepam binding to rat brain synaptosomes with an IC50 of 13.8 μM. Scatchard analysis of the effect of PCALC36 showed a concentration-dependent reduction of the Bmax of [3H]flunitrazepam, without a marked change in Kd. This effect could be reversed by diluting and washing the preparation. Addition of 20-μM GABA shifted to the right the inhibition curve of PCALC36 on [3H]flunitrazepam binding (IC50 ratio of 0.68), which is characteristic for inverse agonists. PCALC36 produced little change in the GABAergic tonic currents recorded by whole-cell patch clamp in cultured rat hippocampal neurones, but it caused a 20% reduction in miniature inhibitory postsynaptic current amplitude and completely antagonised the full (direct) agonist midazolam in a quickly reversible manner. The data suggest that the coumestan backbone can be useful for developing novel ligands at the GABAA receptor.